The morphinan alkaloids represent a family of structurally related natural products of great medicinal importance. An efficient total syntheses of the (−)-morphine and select derivatives has therefore been the objective of many synthetic efforts in the past century. Although a number of routes have been completed, all require long synthetic campaigns through numerous steps resulting in low overall yields and in some cases providing only racemic material. None are suitable for scale-up to a standard manufacturing process. Therefore, a practical method is needed that minimizes the number of steps and intermediate isolations, that is robust; that requires economical reagents and starting materials and that maximizes overall yield. To realize these goals, the methods disclosed in U.S. Pat. Nos. 4,368,326, 4,521,601 5,668,285 to Rice et al. (hereinafter Rice) and H. C. Beyerman, E. Buurman, L. Maat and C. Olieman, Recl. Trav. Chim. Pays-Bas 95, 184 (1976) (hereinafter Beyerman) have been used as basis for a hybrid synthesis into the morphinan ring system primarily focused on improving the key Grewe cyclization step.
Grewe cyclization is a ring closure method that in the present invention utilizes bromine or other halogens as a positional blocking group. The deactivating influence of halogen on the phenolic ring is overcome by the use of “super” acids in the Grewe cyclization (J. Het. Chem. June 1974, 363).
In the Beyerman synthesis, the key intermediate has an additional hydroxyl substitution on the aromatic ring that allows for Grewe cyclization under milder acid conditions, HCl/ethyl ether, but requires a subsequent dehydroxlation step to remove this activating function.
The Rice intermediates that undergo Grewe cyclization contain a methoxy, o-hydroxyl and m-bromo substitution pattern on the aromatic ring. Since these functions do not electron donate as much as three hydroxyls (Beyerman), a “super” acid medium, triflic acid, must be used to form the morphinan ring system. Any water contamination in the triflic acid greatly reduces the yield by the formation of a α,β-bicyclic-ketone and its polymerization by-products. Therefore, the Rice synthesis has a critical cyclization reaction in the middle of the route with very limited, severe, expensive acid requirements.
The dissolving metal reduction reaction well known in the art as the Birch reduction is used for reducing compounds, including the reduction of aromatic compounds to 1,3-cyclohexadiene or 1,4-cyclohexadiene and dehalogenation reactions. Although run under severe reaction conditions, the reduction is an important transformational tool for chemists and has been widely applied in organic synthesis in the partial reduction of an aromatic ring to 1,4-cyclohexadienes or 1,3-cyclohexadienes. Reduction of other functional groups on an aromatic ring or olefin, including the C—X bond, wherein X is a halogen, to C—H usually occurs.
The dissolving metal reduction comprises reacting with an alkali metal in the presence of a nitrogen containing base, usually ammonia. The alkali metal is typically Li, Na, K or Ca in a solvent system including simple alcohols and ethers held at reduced temperature.
The modified reduction reaction utilized in the present invention provides a method for preventing the reduction of at least one halogen substituted aromatic ring of an aromatic compound, while allowing the reduction of at least one functional group on the aromatic compound. This method is the subject of co-pending provisional application Ser. No. 60/534,592, filed Jan. 6, 2004, to the same assignee as the present invention. In this presently preferred method, at least one hydroxyl group and one halogen are substituted on the aromatic ring that does not undergo reduction. The aromatic compound is then reacted with at least one alkali metal in at least one nitrogen containing base and at least one alcohol, while maintaining a ratio of the alcohol to the nitrogen containing base. At least, one halogen substituted aromatic ring with a hydroxyl function is protected from reduction, while the desired group is reduced.
The reaction requires mild reaction conditions for the dissolving metal reduction. The modified metal reduction uses an alkali metal, typically lithium, sodium, potassium, calcium or a mixture thereof as a reductive reagent. The reaction further includes a nitrogen containing base, typically ammonia or a lower amine, and the presence of at least one alcohol. Suitable lower amines include but are not limited to ammonia, methylamine, ethylamine, ethylenediamine and mixtures thereof. The following solvent/nitrogen bases are particularly well suited for the present invention: a mixture of at least one alcohol and ammonia or at least one lower amine, or at least one alcohol, ammonia or at least one lower amine and at least one organic co-solvent. Suitable organic co-solvents include but are not limited to THF, ether and mixtures thereof. The dissolving metal reduction is carried out at a reduced temperature and at a ratio of nitrogen containing base to alcohol at which the reduction or dehalogenation of the protected aromatic ring is prevented. A presently preferred ratio of alcohol to nitrogen containing base is about 1:1 to about 1:4. The reaction temperature is typically maintained at about −30° C. or lower.